1. Field of the Invention
The present invention relates to quality assurance methodologies applied to physiological sample testing devices. More particularly, the present invention relates to an improved quality assurance system and method for point-of-care testing.
2. Background Information
There are several conventional quality assurance methodologies applied to physiological sample testing devices. Where these devices are used on human subjects, the quality assurance process is generally regulated by government, e.g., the Food and Drug Administration (FDA) in the United States of America. For tests and devices that are currently approved for sale over-the-counter to patients, quality assurance is provided by factory testing that provides a usable lifetime or expiration date. In the US, these are termed Clinical Laboratory Improvements Amendments (CLIA) waived tests. Such types of devices provide either qualitative results, as in the case of home pregnancy tests, or quantitative results, as in the case of home blood glucose testing devices. However, the required precision and accuracy of the latter group is not considered to be of the same level of quality as provided by a regulated clinical blood testing laboratory.
Tests and devices that are approved to be used in a clinical laboratory are generally covered by a different set of regulations. Such systems can primarily be categorized as being designed to provide good quality quantitative results, where the reported precision is usually about 10% or better. Skilled users, e.g. clinical laboratory technicians, are required to run the testing systems, and the systems are generally categorized by the regulatory agency as moderately complex. Those skilled in the art will recognize that extensive background information is available at the FDA website. Regarding these systems, there is a current requirement that liquid-based quality control materials are run at regular intervals to ensure that the system is working properly. Such liquid controls are supplied with an expected range of values for a given test. Consequently, when a system is challenged with the liquid control material, the system should report a value within that given range. Where the system reports a result that is out of range, servicing of that system is required. Such a process of quality testing and instrument maintenance is performed by a trained laboratory technician. While it is desirable that any analytical system always runs within specifications, the complexity of this equipment is often at odds with such a desire. It is noted that systems designed by manufacturers for laboratory use have conventionally anticipated that, from time to time, those systems will be out of specification, based on liquid quality control testing, and that technicians are specifically trained to service the system so that it can be brought back into specification.
Over the last several years, a new methodology for blood testing has arisen, termed point-of-care or bedside testing. Such testing is generally performed in a hospital, e.g., emergency room and operating room, but outside of the clinical laboratory. Such testing can also be performed in a physician's office or a temporary or mobile location, e.g., a MASH unit, ambulance, cruise ship, or other like location. Several technologies have been developed for point-of-care testing, and some have the capability of delivering laboratory quality test results (e.g., systems sold by i-STAT Corporation of East Windsor, N.J.). In other words, such point-of-care test systems have the same or substantially similar level of precision and accuracy as achieved in a laboratory test. Such newer systems are generally based on a reader and single-use, disposable test devices or cartridges.
One of the main values of point-of-care blood testing systems is that they have eliminated the time-consuming need to send a patient's blood sample to a central laboratory for testing. These systems are sufficiently easy to operate such that a nurse, at the bedside, can obtain a reliable quantitative analytical result, equivalent in quality to the laboratory. For example, the nurse can select a cartridge with the required panel of tests, draw a blood sample, dispense it into the cartridge, seal the cartridge, and inserts it into the reading device. The reading device then performs a test cycle, i.e., all the other analytical steps required to make the tests. Such simplicity gives the physician more speedy insight into a patient's physiological status. In addition, by reducing the time for evaluation, such point-of-care systems enable a quicker decision by the physician on the appropriate treatment, thus enhancing the likelihood of a successful patient outcome.
In the emergency room and other acute care locations within a hospital, the types of blood tests required for individual patients tends to vary. Thus, point-of-care systems generally offer a range of disposable cartridges with different menus of blood tests. In addition to tests for sodium, potassium, chloride, calcium, partial pressure of oxygen (pO2), partial pressure of carbon dioxide (pCO2), pH, glucose, hematocrit, lactate, blood urea nitrogen (BUN) and creatinine, others tests can include, but are not limited to, prothrombin time (PT), activated clotting time (ACT), activated partial thromboplastin time (APTT), troponin I, troponin T, creatine kinase MB (CKMB), brain natriuretic peptide (BNP), NTproBNP and C-reactive protein (CRP). As is well known in the art, several other parameters can be calculated from these test results, including, for example, base excess (BE) and percentage of oxygen saturation (% O2 sat). These tests can be provided in several combinations presented to the user as a single-use device, e.g., a disposable cartridge. For example, the I-STAT system offers hospitals more than ten types of cartridges with menus that range from one to eight blood tests.
In some cases, cartridges, such as those supplied by i-STAT Corporation, have a shelf-life of about six to about nine months when refrigerated, but only a limited shelf-life, e.g., about two weeks at room temperature, or, more specifically, about two weeks at up to about 30° C. As a result, a hospital will generally store cartridges at a central refrigerated location, and deliver cartridges to specific departments as demand requires. These departments may or may not have available refrigerated storage, and this will affect the inventory they will hold. In certain departments, general storage may be limited, and such a situation will also affect what level of inventory they hold. A given user, such as a hospital, may use multiple types of cartridges and need to ensure the quality of test results at each point-of-care testing location. These locations can include, for example, an emergency room (ER), critical care unit (CCU), pediatric intensive care unit (PICU), intensive care unit (ICU), renal dialysis unit (RDU), operating room (OR), cardiovascular operating room (CVOR) and general wards (GW). Alternatively, the user may be a physician's office laboratory or visiting nurse service. However, the need to ensure quality is the same.
For hospitals, the recent introduction of point-of-care blood testing capabilities has created novel requirements for quality assurance. Such requirements arise from multiple types of disposable blood testing cartridges being used at multiple locations within a given hospital. However, the objective for the hospital is to provide a high level of quality assurance for each type of cartridge at each site of use.
Conventionally, systems offering laboratory quality results were regulated such that some form of liquid quality controls were required to be run by the customer. For example, for the i-STAT system that is based on a handheld reader and single-use cartridges, a statistical sample from a shipment of cartridges is required to be tested by the customer upon receipt. If these cartridges are found to be within specifications, then the whole shipment can be used by the customer for point-of-care testing. For example, one method applied to the i-STAT system, where a particular cartridge type reported results for hematocrit and several blood chemistries, required running four cartridges—two different hematocrit control fluids and two more using two different chemistry control fluids.
More particularly, cartridges are generally supplied by the manufacture to the user in boxes with a given number of units, e.g., twenty-five cartridges of one type. The conventional quality assurance method requires that a statistical sample of these cartridges be tested with control fluids and pass, prior to the remainder being released for use with patient samples. The origins of such a method lay in the historical development of quantitative blood testing systems, where the analytical component, such as a flow cell or cuvette, was re-used many times with different samples. Such reuse could lead to drift in the analytical output, as identified when the system is challenged with control fluids. When the system is shown to be operating outside specifications, servicing is required. As these systems were generally located in a central hospital laboratory, skilled technician trained specifically for this purpose provided the servicing.
Such a general type of liquid control testing is appropriate for many laboratory-based systems where the same detector, such as an optical cuvette chamber and electrode, is re-used many times in making a measurement. For example, a traditional blood gas analyzer that has an array of electrodes (e.g., pH, pCO2, pO2, and the like) can pass though many repeated test cycles where a calibrant fluid or gas is applied, then the sample, and finally a wash fluid. Such electrodes over time can become fouled with residual sample components (e.g., protein or the like), despite performance of the automatic wash step after each sample is run. Here, the intermittent use of liquid controls helps to ensure that a system where a repeatedly used component (e.g., an electrode) that has drifted out of specification is identified and corrected within a period of several hours. By contrast, a system that is based on electrodes or other detection devices that are only used once and then discarded, such as in the i-STAT system, does not experience the kind of drift during use common to reusable detection devices.
As one skilled in the art will recognize, during the development of a testing system, performance characteristics will be determined. Precision data are generally collected at multiple test sites and a method comparison performed versus one or more commercially established systems. Typically, a Deming (or General Deming) regression analysis is used to provide estimates of imprecision between the new and old methods and to provide a standard error of estimates (Sy.x) and correlation coefficient (r), as described in, for example, P. J. Combleet and N. Gochman, “Incorrect Least Squares Regression Coefficients in Method-Comparison Analysis,” Clinical Chemistry 25:3, 432 (1979); and R. F. Martin, “General Deming Regression for Estimating Systematic Bias and Its Confidence Interval in Method-Comparison Studies,” Clinical Chemistry 46:100-104 (January 2000).
Precision data for the control fluids are also determined to provide a mean (M), standard deviation (SD), and percent coefficient of variation (% CV). By way of example, the following table summaries precision data for the aforementioned i-STAT system for various tests using control fluids at different levels. These values are illustrative of laboratory quality systems delivering quantitative results to a precision of about 10% or better.
TABLE 1Precision Data for the i-STAT SystemAqueous ControlMeanSD% CVLevel 1 potassium2.85mM0.0381.33Level 3 potassium6.30mM0.0390.62Level 1 sodium120.0mM0.460.38Level 3 sodium160.0mM0.530.33Level 1 glucose41.8mg/dL0.681.63Level 3 glucose289mg/dL2.400.83Level 1 BUN5.5mg/dL0.458.18Level 3 BUN52.8mg/dL0.761.44Level 1 chloride76.7mM0.540.70Level 3 chloride114.0mM0.560.49Level 1 hematocrit30%0.441.47Level 3 hematocrit49%0.501.02Level 1 calcium0.84mM0.0121.43Level 3 calcium1.6mM0.0171.06Level 1 creatinine0.76mM0.056.58Level 3 creatinine4.7mM0.081.70Level 1 TCO218.2mmHg0.211.15Level 3 TCO238mmHg0.411.08Level 1 lactate0.81mM0.033.70Level 3 lactate6.35mM0.081.26Level 1 pH7.1650.0050.07Level 3 pH7.6560.0030.04Level 1 pCO219.6mmHg0.402.04Level 3 pCO263.8mmHg1.572.46Level 1 pO265.1mmHg3.124.79Level 3 pO2146.5mmHg6.004.10Level 1 ACTc221seconds18.008.10Level 3 ACTc456seconds22.004.80Level 1 ACTk169seconds4.002.00Level 3 ACTk409seconds21.005.20Level 1 PT1.1seconds0.054.50Level 3 PT2.5seconds0.176.90Level 1 cTnI0.53ng/mL0.047.80Level 3 cTnI31.82ng/mL2.427.60Level 1 CKMB5.90ng/mL0.7011.9Level 3 CKMB25.80ng/mL2.7010.4Level 1 BNP126pg/mL—9.0Level 2 BNP1551pg/mL—6.6Level 3 BNP3337pg/mL—8.0
For example, a conventional method of performing quality assurance, such as that used by the i-STAT system, for cartridges comprising tests for blood chemistries and hematocrit is as follows. Cartridges are shipped from the manufacture with an ice-pack in an insulated box to arrive at the customer within two business days. Within the box is a temperature strip containing a red wax that changes color if it has experienced a temperature elevation for a certain time. If this occurs, the user is instructed to either return the shipment or call the supplier for further instructions. Assuming the cartridges arrive safely and the temperature strip has not been triggered, then the cartridges are transferred to refrigerated storage. At this point, four cartridges are removed and checked with four different control fluids. Such checking is performed with two control fluids that represent different chemistry values and two control fluids that represent two different hematocrit levels. If all four cartridges report results consistent with the expected values for the controls, then the rest of the cartridges are available for release from storage to be sent to one or more point-of-care locations.
While such a method of operation is generally acceptable for point-of-care locations within large institutions, such as, for example, a hospital or the like, that use a substantial number of cartridges per year, it is less suitable for other point-of-care locations, such as a physician's office. In particular, a physician generally orders less cartridges and uses them at a lower rate than a hospital. As a result, the performance of running liquid controls on single-use test devices intended to give laboratory quality results at the point-of-care can be burdensome on certain customers, and can in certain circumstances reduce the desirability of using the technology. Consequently, there remains a need for a quality testing methodology for the physician's office and other low volume point-of-care users (e.g., nursing homes) that is simpler to manage. In addition, the development of newer testing systems based on single-use analytical devices, in combination with the desire to provide testing services right at the point of patient care, has generated a need for quality control methodologies that better meet the needs of point-of-care testing. As a result, there remains the need for an improved means for providing quality assurance, preferably without the need for using liquid quality controls by the customer. Furthermore, there remains a need for an improved means for providing quality assurance that significantly reduces the number of liquid quality controls used by the customer.